The Daily Sign-Outtag:typepad.com,2003:weblog-18025122014-06-25T07:07:00-05:00Surgical pathology primarily focus on lung, cancer research, and transfusion medicine for pathologists, oncologists, surgeons and patients.TypePadNHLBI Workshop Report: Matrix Biology in Idiopathic Pulmonary Fibrosistag:typepad.com,2003:post-6a010536c71c0f970c01a511d4698e970c2014-06-25T07:07:00-05:002014-06-25T07:07:00-05:00The June 2014 issue of American Journal of Pathology has this state-of-the-art review, based on a recent NHBLI workshop, of the various attributes of the lung extracellular matrix and its role in normal lung and in the development of IPF....Mark D. Pool, M.D.

The June 2014 issue of American Journal of Pathology has this state-of-the-art review, based on a recent NHBLI workshop, of the various attributes of the lung extracellular matrix and its role in normal lung and in the development of IPF.

This is an "open access' (FREE) article and you can get CME for it too!

Here's a choice figure that nicely summarizes the biochemical and mechanical interactions between the fibroblast and the ECM:

NKX2-1/TTF-1 drives pulmonary-specific differentiation in lung adenocarcinomatag:typepad.com,2003:post-6a010536c71c0f970c017eeaee5423970d2013-05-08T15:08:47-05:002013-05-08T15:08:47-05:00Snyder et al. recently published an intriguing report in Molecular Cell (21 March 2013) (featured free article) in which they convincingly demonstrate how tumors in which Nkx2-1 was deleted show striking different morphology from those in which Nkx2-1 is expressed....Mark D. Pool, M.D.

Snyder et al. recently published an intriguing report in Molecular Cell (21 March 2013) (featured free article) in which they convincingly demonstrate how tumors in which Nkx2-1 was deleted show striking different morphology from those in which Nkx2-1 is expressed.

Nkx2-1/TTF-1 is
a highly conserved homeodomain-containing transcription
factor that is expressed at the onset of lung and thyroid development and has been shown from murine knockout experiments to be required for branching morphogenesis in very early lung development. Nkx2-1 is expressed in about 80% of human lung adenocarcinomas (ADCs). Recent studies have shown that Nkx2-1-negative ADCs have a worse prognosis and have a higher histologic grade (more poorly differentiated) compared to Nkx2-1-positive tumors. These data suggest that Nkx2-1 may coordinate a
lineage-specific differentiation program on lung adenocarcinomas that restrains their malignant potential. Further data have shown that the Nkx2-1
gene is amplified in 10%–15% of human lung ADCs, suggesting that it can also act as a lineage-survival oncogene in a subset of tumors. The authors' previous work using a mouse model for lung ADC showed that Nkx2-1 restrained the ability of Kras-driven
lung tumors to evolve to a poorly differentiated, Hmga2-positive state.

The authors cleverly designed a mouse model in which Cre recombinase can activate a conditional allele of Kras G12D and delete both alleles of Nkx2-1 from the lungs of mice. Simultaneous activation of Kras G12D and deletion of Nkx2-1 yielded peripheral lung ADCs that showed a distinct glandular growth pattern of malignant cells with abundant MUC5A-positive mucin resembling human lung mucinous ADC. In contrast, control Nkx2-1-positive mice developed tumors showing a predominantly papillary non-mucinous pattern. They also showed in a different model that in established tumors, Nkx2-1 deletion induced a glandular pattern and mucin production similar to de novo tumors and promoted long-term tumor growth. In addition, this study demonstrated that Nkx2-1 deletion induced diffuse alveolar epithelial hyperplasia in the alveolar space. The hyperplastic cells lacked expression of canonical Nkx2-1 targets and exhibited increasing mucinous accumulation and morphology over time.

The authors compared Kras-mutant/Nkx2-1-deleted tumors and Nkx2-1-positive
tumors by mRNA expression profiling and found 1,828 differentially expressed genes, including 1,137 upregulated and 691 downregulated genes. MetaCore analysis for disease-specific gene
collections and networks identified genes associated with gastric diseases that were enriched in ‘‘stomach neoplasms’’ and
‘‘stomach diseases’’ as categories that were enriched in Kras-mutant/Nkx2-1-deleted
tumors. Finally, they determined whether human mucinous lung adenocarcinomas also exhibit evidence of gastric differentiationby evaluating the expression
of two stomach-restricted proteins (GKN1 and CTSE) in 37
human lung adenocarcinomas. In 11 NKX2-1-negative mucinous
human lung adenocarcinomas (n = 11), they found that GKN1
was expressed in 6 out of 11 cases and that CTSE was strongly
and diffusely expressed in all 11 tumors. In
contrast, NKX2-1-positive lung adenocarcinomas (n = 26) were
entirely negative for GKN1. Most NKX2-1-positive lung tumors
were either negative (n = 14) or only focally positive (n = 10) for
CTSE.

The DL

There is much more to unpack from this article than I can concisely summarize in this post. The fascinating point for me is that lung alveolar epithelial cells have a latent gastric differentiation program that becomes activated by default when Nkx2-1/TTF-1 is deleted and this is most dramatically evinced in pulmonary mucinous adenocarcinomas. These particular tumors are nettlesome diagnostically because of the question raised of whether the tumor is primary or metastatic.

Wonderful paper and lots to think about!

Fetal Lung Interstitial Tumor--report of proposed new entitytag:typepad.com,2003:post-6a010536c71c0f970c0147e1b757e5970b2011-02-02T06:37:00-06:002011-01-31T21:13:58-06:00So many great articles at the end of the year, it's going to take me 'til Easter to catch up! The December 2010 issue of American Journal of Surgical Pathology has a fascinating article from Dishop and (multiple) colleagues reporting...Mark D. Pool, M.D.

So many great articles at the end of the year, it's going to take me 'til Easter to catch up!

The December 2010 issue of American Journal of Surgical Pathology has a fascinating article from Dishop and (multiple) colleagues reporting 10 morphologically distinct tumors from multiple American institutions. The patients' ages ranged from 0 days to 3 months and imaging in each case revealed a well-circumscribed lobar-based mass. Lobectomy or wedge resection was performed in each case.

Each tumor was a well-circumscibed intraparenchymal mass with a solid-to-spongelike surface that appeared to be at least partially surrounded by a fibrous capsule. The microscopic appearance was characterized by an abrupt transition from normal saccular-stage lung to more immature-appearing, variably-sized and -shaped spaces separated by cellular septa with variable width. The lining epithelium is composed of regularly distributed non-ciliated flattened to cuboidal cells. The interstitium is composed of a monotonous population of uniformly distributed round-to-ovoid mesenchymal cells. None of the cases showed any of the malignant features associated with pleuropulmonary blastoma (PPB).

The interstitial cells showed diffuse positivity for vimentin and variable staining for smooth muscle actin and desmin; the epithelial cells were positive for cytokeratin (clone not specified) and EMA but TTF-1 positivity was reported in only 1 case.

Fetal lung interstitial tumor (FLIT) is the term proposed by the authors to describe a lobar-based tumor well-demarcated from surrounding normal lung that presents either prenatally or within the first 3 months of age, is composed of variably sized cysts composed of histologically benign epithelium and interstitial cells, and shows apparently benign clinical behavior.

The authors discuss the possible relationship between "FLIT," type I (cystic) PPB, and congenital peribronchial myofibroblastic tumor (CPMT) and posit a growth disorder in pulmonary interstitial cells as a common histogenesis for these rare, curious tumors.

I realize that this is a highly subspecialized report that is probably of little general interest. BUT check this: tumors such as these point to the complex interactions between endodermally-derived epithelium and mesodermally-derived mesenchyme during lung development--an interaction which plays itself out again in more common lung diseases, like ILDs and lung cancer!

New data challenges assumptions about smoking and lung cancertag:typepad.com,2003:post-6a010536c71c0f970c013485e4acc6970c2010-08-02T09:00:00-05:002010-07-31T12:44:31-05:00Data presented at the recent 11th International Lung Cancer Congress challenges the commonly accepted notion that most lung cancer patients are current smokers or only recently quit after the onset of lung cancer-related symptoms. A retrospective study of 626 lung...Mark D. Pool, M.D.

Data presented at the recent 11th International Lung Cancer Congress challenges the commonly accepted notion that most lung cancer patients are current smokers or only recently quit after the onset of lung cancer-related symptoms. A retrospective study of 626 lung cancer patients treated at a tertiary care center reported that 77% of patients had a smoking history--but only 14.7% were smoking at the time of diagnosis. Moreover, 60% of the remaining patients with a smoking history had not smoked for a mean of 18 years--and the other 40% had stopped smoking within 10 years of diagnosis. The research team was led by Dr. Cindy Mong from UCLA-David Geffen School of Medicine.

In addition, a relationship between the time interval of smoking cessation and tumor histologic type was identified: patients were significantly more likely to have adenocarcinoma if more than 21 years had elapsed since they last smoked, while squamous cell carcinoma was more common in current smokers. Interestingly, the prevalence of ACa varied inversely with the number of pack-year history.

This is intriguing (albeit somewhat discouraging) data, although it is unclear how representative these results are compared to the general population or to other areas of the U.S. There is a referral bias toward non-smokers in this study compared to information about the general U.S. population (23% non-smokers in this study versus 9% in general) as well as an overrepresentation of lower stage patients in this study. According to 2008 data from the CDC, only 16% of patients in the U.S. were diagnosed with localized disease compared to 59% in this study.

Nevertheless, these data are striking and, if generalized to the entire population, have long-term consequences for patients and oncology care--not to mention important health care policy implications. Too bad we burned through all that tobacco litigation money. We will have to do a massive education effort for patients who have ever smoked that they will be at risk for cancer for years after they quit.

Mutations amok in lung cancertag:typepad.com,2003:post-6a010536c71c0f970c0134821cbdb4970c2010-05-27T15:30:00-05:002010-05-27T15:30:00-05:00A team from Genentech reports their findings in this week's Nature 465, 473-477 (27 May 2010) of direct tumor sequencing of a 51-year-old man with a 19-pack-year smoking history. Note the greater than 50,000 mutations compared with paired "normal" lung....Mark D. Pool, M.D.

A team from Genentech reports their findings in this week's Nature465, 473-477 (27 May 2010) of direct tumor sequencing of a 51-year-old man with a 19-pack-year smoking history. Note the greater than 50,000 mutations compared with paired "normal" lung. (egads!!!) Not surprisingly, they found mutation of KRAS. The magnitude and breadth of mutations is staggering and was surprising to the researchers. Certainly give pause to ongoing efforts to identify oncogene-addicted tumors amenable to targeted therapy.

excerpt from abstract:

Here we present the complete sequences of a primary lung tumour (60×
coverage) and adjacent normal tissue (46×). Comparing the two genomes,
we identify a wide variety of somatic variations, including >50,000
high-confidence single nucleotide variants. We validated 530 somatic
single nucleotide variants in this tumour, including one in the KRASproto-oncogene and 391 others in coding regions, as well as 43
large-scale structural variations.

HealthDay has a nice accompanying article with an interview of the PI.

Evidence for stem/progenitor cells in mouse lung modeltag:typepad.com,2003:post-6a010536c71c0f970c0128773e286b970c2010-02-01T06:35:08-06:002010-02-01T06:35:08-06:00I came across this excellent paper and summarized my "top 10 list" of points from the paper. The role of stem/progenitor cells in cancer is a crazy-active area in current research. If you catch some of the details, you can...Mark D. Pool, M.D.

I came across this excellent paper and summarized my "top 10 list" of points from the paper. The role of stem/progenitor cells in cancer is a crazy-active area in current research. If you catch some of the details, you can probably guess the technical challenges to this work.

Evidence of an epithelial stem/progenitor cell hierarchy in the adult mouse lung

Lung epithelial cells comprise less than 0.05% of lung epithelial cells and are predominantly restricted to the EpCAMhi CD49fpos (α-6-integrin) cell fraction.

The EpCAMhi cell fraction was exclusively CD104pos (β-4 integrin).

In the adult mouse lung, immunofluorescent staining demonstrated that CD104 has a distinct localization to endothelial cells and the basal plasma membrane of virtually all epithelial cells in the bronchi and most cells in the terminal bronchioles.

Further enrichment of epithelial cfus in the EpCAMhi cell fraction was achieved by selecting on the basis of high or low expression of CD24 (heat-stable antigen) the incidence of colony formation is directly proportional to the number of CD24low cells plated and that the cloning efficiency of this population is only about 4.5%

Only CD24low cells demonstrate cfu potential, suggesting that only a restricted subpopulation of EpCAMhi CD49fpos CD104pos CD24low bronchiolar epithelial cells have the capacity to serve as stem/progenitor cells

This is at variance with previous reports suggesting that the majority of Clara cells in the bronchioles can self-renew and generate differentiated progeny (13). The relation of the authors EpCAMhi CD24low population to the Clara or variant Clara cell is unclear (3) and will require identification of previously undescribed Clara cell markers for further subsetting.

Lung epithelial cfus are clonally derived and a subset of EpCAMhi CD104pos epthelial cfus possess the capacity for in vitro self-renewal after serial passage.